Biology subjects

Scott, E.

Publications and source records attributed to Scott, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Site Specific Hydration Contributes to the Thermal Stability of Proteins and Protein-Complexes

Water is integral to protein structure and stability, yet ensemble measurements rarely identify the hydration interactions associated with stabilization. Here, variable-temperature electrospray ionization ion mobility mass spectrometry, conformation-resolved thermodynamic analysis, and molecular dynamics simulations are combined to examine solvent-dependent thermal stability of chymotrypsin inhibitor 2 (CI-2), a model two-state folder, and the barnase-barstar (Bn-B*) complex, which contains a highly polar binding interface. Replacing H2O with D2O raises the thermal transition temperature of both systems by approximately 3 {degrees}C, favors compact conformations, and reduces the relative thermodynamic accessibility of extended states. The conformationally resolved enthalpy-entropy compensation reveals D2O increases enthalpy for CI-2 but reduces enthalpy for Bn-B* as a result of opposing effects on the individual subunits of the complex. Molecular dynamics simulations reveal that lower solvent-accessible surface areas and fewer protein-water hydrogen bonds in D2O coexist with longer water residence times at specific structural sites. In CI-2, the strongest changes localize to the second {beta}-strand/C-terminal region; in Bn-B*, persistent hydration is concentrated at the charged protein-protein interface. Together, these results support a model in which D2O dependent stabilization is associated not only with the extent of hydration, but the site and lifetime of water interactions. More broadly, this work provides an experimental framework for resolving solvent-dependent conformational thermodynamics of protein unfolding and interactions, enabling direct comparison of free-energy landscapes across solution environments.

biochemistry↗

bioRxiv2026

Programming Brain Cell-Type-Selective Delivery In Vivo with Transporter-Guided Therapeutics

Many diseases arise from dysfunction of defined cell populations, yet most therapeutics distribute broadly, limiting efficacy and causing toxicity. We developed ExACT, a platform for cell-type-selective intracellular delivery that exploits membrane transporters. In vivo screening of combinatorial fluorescent small-molecule libraries in mouse brain identified chemistries whose uptake is dictated by endogenous transporter expression, yielding compounds with preferential entry into neurons, astrocytes, pericytes and endothelial cells. One series showed strong selectivity for brain and retinal endothelium, where Slco1a4 mediated uptake. This selectivity principle extended to the human orthologue SLCO1A2, highly expressed in brain endothelium and oligodendrocytes, where it mediated selective uptake in a humanized mouse model and human iPSC-derived oligodendrocytes. Ectopic expression of SLCO1A2 in neurons via gene therapy created a synthetic entry port, conferring ExACT conjugate uptake on otherwise inaccessible cells. Bifunctional compounds linking transporter-targeting motifs to antisense oligonucleotides or small-molecule drugs retained pharmacological activity while conferring transporter-dependent cell-type selectivity, illustrating how transporter diversity can be harnessed for precision pharmacotherapy.

bioengineering↗

bioRxiv2026

Whole-brain cellular-resolution functional network properties of seizure susceptibility

Despite its prevalence and clinical impacts, epilepsy remains incompletely understood in terms of the population dynamics that mediate seizure susceptibility, initiation, and propagation across brain-wide networks. In this study, we have performed calcium imaging in zebrafish, brain-wide and at cellular resolution, at baseline and as seizures are induced using the GABAA receptor antagonist pentylenetetrazol (PTZ). We have then modeled the network architecture in wild-type and scn1lab-/- larvae, which are seizure-prone and serve as a model for Dravet syndrome. scn1lab-/- larvae show increased pair-wise correlations between neurons when exposed to PTZ, and graph analyses of these correlations revealed genotype-specific network alterations during seizures, identifying regions and metrics linked to seizure onset. Using generative network modeling, we then explored the wiring rules that govern activity in these networks, identifying specific network properties linked to seizure susceptibility that were only detectable using large-scale, cellular-resolution data. Even at baseline in the absence of seizures, these rules differed by genotype in a way that enabled the identification of scn1lab-/- larvae and predicted individuals seizure risk independently of their observable phenotype. These findings uncover the cellular-resolution network properties of a zebrafish model of Dravet syndrome and establish a predictive framework for seizure susceptibility grounded in multi-scale functional connectivity.

neuroscience↗

bioRxiv2026

Cellular mechanisms underlying social regulation of the posterior tubercular nucleus in zebrafish (Danio rerio)

Social status profoundly influences animal behavior through neural plasticity, yet the cellular mechanisms that mediate reconfiguration of neuromodulatory systems remain poorly understood. Here, we investigated status-dependent structural changes in the posterior tubercular nucleus (PTN) of adult zebrafish. Animals were assigned to four social conditions: communal, isolated, dominant, or subordinate. Using markers for cell proliferation (PCNA) and birth-dating (BrdU), we demonstrate that social dominance significantly enhances cell proliferation, leading to an increased population of PTN dopaminergic neurons. In contrast, subordinate and isolated fish exhibited suppressed proliferation and elevated expression of superoxide dismutase 1 (SOD1), suggesting that chronic social stress induces an oxidative burden that may lead to neuronal loss. Furthermore, we identified evidence of neurotransmitter phenotypic plasticity; subordinate fish displayed a significantly higher ratio of glutamatergic (vglut2a) to dopaminergic (dat) expression in PTN neurons compared to dominants, suggesting a status-dependent shift in neuromodulatory identity. Multivariate principal component analysis showed distinct neurobiological profiles that separate social ranks, suggesting that status-dependent plasticity is a coordinated multi-modal response whereby increased BrdU and PCNA expression clustered with the dominant profile while increased expression of cellular stress and shift to glutamate cellular identity clustered with social subordinate and isolate profiles. Collectively, our results improve our understanding of how social experience reshapes the zebrafish brain through integrated changes in cell proliferation, cellular shift in neurotransmitter identity and regulation of cellular viability; thus, providing a potential mechanism for the maintenance of stable behavioral phenotypes in competitive social environments.

neuroscience↗

bioRxiv2025

Xeno-free human iPSC-derived prostate organoid platform for multilineage differentiation and genetic manipulation

Current prostate organoid models rely on tissue-derived material or animal components and lack epithelial and stromal complexity. We defined a xeno-free system to generate human prostate organoids from induced pluripotent stem cells with consistent multilineage differentiation. Floating organoids self-organize into epithelial and stromal domains with basal, luminal, neuroendocrine, fibroblast, and smooth muscle markers. In an alternative modular co-culture system, engineered epithelial progenitors are aggregated with wild-type mesenchymal progenitors, enabling compartment-specific manipulation. Androgen receptor-overexpressing organoids showed increased epithelial AR and PSA expression and proliferation. Single-cell transcriptomics, together with qPCR and immunostaining, confirmed prostate lineage specification and tissue organization. This new xeno-free platform provides a reproducible, scalable, and genetically tractable model to study in-vitro prostate lineage programs, epithelial-stromal interactions, and disease biology. Graphic AbstractThis study describes the generation of prostate organoids from human iPSCs. iPSCs, including those reprogrammed from patients carrying germline mutations, can be differentiated into prostate organoids either through monoculture or by co-culturing endodermal cells with mesenchymal progenitors. Genetic manipulation can be introduced before endoderm specification to model cancer drivers. The resulting multi-lineage organoids exhibit distinct epithelial (AR, NKX3.1, PSA, CK8/18) and stromal (VIM, -SMA) compartments, providing a versatile platform for developmental studies, disease modelling, drug screening, and biomarker discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/683654v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1cc13eborg.highwire.dtl.DTLVardef@12fe2a4org.highwire.dtl.DTLVardef@c89d64org.highwire.dtl.DTLVardef@d541e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

The Androgen Receptor and MYC synergise to modulate the synthesis of Siglec-7 ligands in prostate cancer

Glyco-immune checkpoints have recently been shown to be critical mediators of immunotherapy resistance across multiple cancer types. In clinical trials, immunotherapeutic treatments for prostate cancer have failed to elicit durable clinical responses. PCa progression is driven by transcriptional networks regulated by key transcription factors including the androgen receptor (AR) and the oncogene MYC. How this crossover between hormone and oncogene-driven signalling pathways regulates tumour glyco-immune checkpoints remains unclear. Here, we show that O-glycans are the major substrates for sialylation in prostate cancer and that sialyltransferases that have preferences for O-glycans are differentially regulated by androgens. We show that supraphysiological levels of androgens produce distinct glycopeptide profiles in prostate cancer cells compared with cells exposed to physiological androgens. Additionally, we identify a direct and coordinated role for AR and MYC in regulating ST3Gal1 and the synthesis of Siglec-7 ligands in prostate cancer. Both transcription factors converge to repress ST3GAL1, thereby limiting the generation of Siglec-7 ligands. These findings highlight a context-dependent, cooperative relationship between the AR and MYC in shaping the tumour sialome, linking hormonal signalling and oncogenic transcription to Siglec biology. Our study highlights how cell-type specific differences in transcriptional networks has important downstream effects for immune modulating glycans and has tumour specific clinical implications.

cancer biology↗

bioRxiv2025

Software System Design to Support Scale in Mammalian Cell Line Engineering.

Cell line engineering (CLE) is the process of gene editing cell lines for a variety of purposes for research and development or bioproduction processes. Traditionally, CLE workflows have been manual and low throughput. Here, we describe the development of several software-based processes implemented alongside wet-lab automation and robotics, built to improve the throughput of our CLE platform to three times its previous capacity. A markup language (GEML) was developed to enable eCommerce capabilities and connections to internal manufacturing systems. A Laboratory Information Management System (LIMS) specifically designed to track CLE projects through all stages was created to manufacture the cell line specified by the GEML. Cell line engineering required analysis of images in brightfield without fluorescent staining therefore a machine learning (ML)-based method for analysing engineered clones imaged captured on an automated imaging platform was created. Our work demonstrates that combining both wet-lab automation and software approaches is essential to allow CLE workflows to reach their full potential, allowing the development of high-throughput robust platforms that meet the increasing demands of the field.

synthetic biology↗

bioRxiv2025

Predicting the responses of the world's bird species to increases in agricultural production

The intensification and expansion of croplands are among the greatest threats to biodiversity, but the likely responses to these changes remain unknown for most species. Using data on responses of 862 bird species to changes in yields of arable crops, we extrapolate vulnerability to agriculture for the worlds other terrestrial birds based on their traits and taxonomy. We estimate that 74-78% of terrestrial bird species globally suffer population declines where natural habitats are replaced by croplands, and that over half cannot persist in cropland at even the lowest current yields. Past impacts of agriculture on birds have been greatest in the tropics, particularly in coastal forest regions of Central and South America and West Africa and in southern and South-East Asia. Using these estimates to model the impacts of future scenarios of agricultural change, we find that continuing current rates of cropland expansion and yield increases (i.e., extrapolating business-as-usual trends to 2050) is expected to have more negative impacts on birds (particularly in Central and South America, Eastern Europe, sub-Saharan Africa and South and East Asia) than a potential alternative of a targeted strategy of closing yield gaps while limiting cropland expansion. However, we also identify biodiverse regions of the world where closing yield gaps may have more severe impacts on birds than business-as-usual, such as the Pampas of South America and parts of the Sahel region in West Africa. The strategy of least impact for a particular area can be predicted from the response characteristics of the communities of species present there, offering opportunities to take account of regional context for designing less damaging global food production systems.

ecology↗

bioRxiv2025

KV1.8 (Kcna10) potassium channels enhance fast, linear signaling in vestibular hair cells and facilitate vestibulomotor reflexes and balance

Vestibular hair cells (HCs) faithfully and rapidly detect head motions and gravity, driving motor reflexes that stabilize balance and gaze during locomotion. With the transition from water to land, the amniote vestibular inner ear added type I HCs, which differ from amniote type II HCs and anamniote HCs by their large calyx afferent synapse, non-quantal afferent transmission, and a large, low-voltage-activated K+ conductance (gK,L). We recently showed that both gK,L and the major type II K+ conductances (A-type and delayed rectifier) require KV1.8 (Kcna10) subunits. Here we compared KV1.8-null (Kcna10-/-) and control animals to see how KV1.8 affects function as measured by receptor potentials and nonquantal postsynaptic potentials evoked by direct hair bundle motions, and by vestibulomotor behaviors. Recordings were taken from extrastriolar zones of the utricle. In both HC types, KV1.8 affected receptor potentials by reducing response time and gain, increasing dampening, and expanding the frequency bandwidth toward high frequencies. Effects are most prominent in type I HCs: lowpass corner frequencies of receptor potentials in Kcna10-/- HCs of both types were [~]20 Hz, vs. [~]400 Hz in control type I and [~]70 Hz in control type II. We recorded nonquantal postsynaptic potentials from extrastriolar calyces, and found that the synaptic transfer function had lower gain and greater phase lag in Kcna10-/- mice. In behavioral tests, Kcna10-/- mice had vestibular-ocular reflexes with different response dynamics at low frequencies, impaired performance on a narrow balance beam, abnormal body posture and abnormal head motions in water and on land, and also rarely assumed bipedal stances. These vestibulomotor deficits in Kcna10-/- mice likely reflect the changes noted in HCs, where KV1.8 expression is concentrated; that is, slower signaling of high-frequency head motions by Kcna10-/- HCs fails to fully stabilize body and head position during locomotion. Thus, gK,L (KV1.8) contributes to fast signal transmission in the amniote vestibular inner ear and supports improved performance on challenging vestibulomotor tasks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/634388v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@126570borg.highwire.dtl.DTLVardef@1cab5borg.highwire.dtl.DTLVardef@36240corg.highwire.dtl.DTLVardef@789617_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Stable primary brain cell cultures from zebrafish reveal hyperproliferation of non-neuronal cells from scn1lab mutants

Zebrafish are a popular model system for studying the genetic and neural underpinnings of perception and behavior, both in wild-type animals and in the context of disease modelling. Cultured primary neurons provide a key complementary tool for such studies, but existing protocols for culturing embryonic zebrafish primary neurons are limited by short cell survival and low neuronal purity. In this study, we set out to establish a protocol to produce long lived, pure neuronal cultures from zebrafish that could be used to study the mechanistic contributions of genes to neuronal networks. We then used these primary cultures to characterize cell proliferation and differentiation in primary neurons derived from scn1lab mutant embryos, which lack a sodium channel relevant to Dravet syndrome and autism. Using our optimized protocol, we generated cultures that proliferate, diversify, and form stable networks of neurons surviving for months. These stable cultures allowed us to perform genetic experiments, in this case revealing dramatic differences in the cellular composition of cultures derived from scn1lab mutant embryos versus their wild type siblings. Specifically, we find that loss of scn1lab promotes hyperproliferation of non-neuronal cells in mixed cultures of brain cells. In pure neuronal cultures, we find alterations in neurotransmitter subtypes consistent with known effects of scn1lab loss of function. Validating the utility of this approach, we then identify a corresponding hyperproliferation phenotype in live scn1lab mutant embryos, shedding light on potential mechanisms that may be relevant for Dravet syndrome. Significance statementMost existing embryonic zebrafish primary neuron culture protocols describe growing mixed cell types for restricted durations. Here, we report generation of zebrafish mixed type or pure neuronal cultures that are viable for over 100 days. We apply these cultures to gain new insight into scn1lab, a zebrafish orthologue of the Dravet Syndrome-associated sodium channel gene SCN1A. We report that loss of scn1lab results in hyperproliferation of non-neuronal cells, revealing an underappreciated mechanism by which mutations in SCN1A impact the structure and function of neuronal networks. Our in vitro cultures thus faithfully recapitulate in vivo neurobiology and provide a powerful platform to interrogate brain function in health and disease.

neuroscience↗

bioRxiv2024

Phylogenetically-Preserved Multiscale Neuronal Activity: Iterative Coarse-Graining Reconciles Scale-Dependent Theories of Brain Function

Brain recordings collected at different resolutions support statistically distinct signatures of information processing, leading to scale-dependent theories of brain function. Here, we demonstrate that these disparate neural-coding signatures emerge from the same multiscale functional organisation of neuronal activity across calcium-imaging recordings collected from the whole brains of zebrafish and nematode, as well as sensory regions of the fly, mouse, and macaque brain. Network simulations show that hierarchical-modular structural connectivity facilitates multiscale functional coordination, enhancing information processing benefits such as a maximal dynamic range. Finally, we demonstrate that this cross-scale organisation supports distinct behavioural states across species by reconfiguring functional affiliation and temporal dynamics at the mesoscale. Our findings suggest that self-similar scaling of neuronal activity is a universal principle that reconciles scale-dependent theories of brain function, facilitating both efficiency and resiliency while enabling significant reconfiguration of mesoscale cellular ensembles to accommodate behavioural demands.

neuroscience↗

bioRxiv2023

Rapamycin mitigates Valproic Acid-induced teratogenicity in human and animal models by suppressing AP-1-mediated senescence

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs at the expense of neural lineages. We next show that the clinically-approved drug, Rapamycin, inhibits AP1-mediated senescence and restores aberrant NCC differentiation trajectory in human organoids exposed to VPA. Notably, in vivo validation in developing zebrafish highlighted the therapeutic promise of this approach. Collectively our data identifies a novel mechanism for VPA-associated neurodevelopmental teratogenicity and a potential pharmacological preventative strategy. The results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery and safety testing.

neuroscience↗

bioRxiv2023

ST3Gal1 synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer

Immune checkpoint blockade trials have yet to produce a robust anti-cancer response in prostate cancer patients as a monotherapy due to the immunosuppressed prostate cancer tumour immune microenvironment. ST3Gal1 and other sialyltransferases are implicated in cancer and immune suppression by synthesizing sialoglycans, which act as ligands for Siglec receptors. These checkpoints are important for the immune response. However, its unclear how the synthesis of Siglec ligands is regulated, and little is known about the role of sialoglycan-Siglec-axis in prostate cancers evasion of anti-tumour immunity. We report that ST3Gal1 levels negatively correlate with androgen signalling in prostate tumours. Utilising syngeneic mouse models, we demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion. Using mouse models, patient samples and in vitro models we show that ST3Gal1 synthesises sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. For the first time we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. Importantly, we show that these interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.

cancer biology↗

bioRxiv2023

The effects of social experience on host gut microbiome in male zebrafish (Danio rerio)

Although the gut and the brain vastly differ in physiological function, they have been interlinked in a variety of different neurological and behavioral disorders. The bacteria that comprise the gut microbiome communicate and influence the function of various physiological processes within the body including nervous system function. However, the effects of social experience in the context of dominance and chronic stress on gut microbiome remain poorly understood. Here, we examined whether social experience impacts the host zebrafish (Danio rerio) gut microbiome. We studied how social dominance during the first two weeks of social interactions changed the composition of zebrafish gut microbiome by comparing gut bacterial composition, diversity and relative abundance among socially dominant, submissive, social isolates, and control group-housed communal fish. Using amplicon sequencing of the 16S rRNA gene, we report that social dominance significantly affects host gut bacterial community composition but not bacterial diversity. At the genus-level, Aeromonas and unclassified Enterobacteriaceae relative abundance decreased in dominant individuals while commensal bacteria (e.g., Exiguobacterium and Cetobacterium) increased in relative abundance. Conversely, the relative abundance of Psychrobacter and Acinetobacter was increased in subordinates, isolates, and communal fish compared to dominant fish. The shift in commensal and pathogenic bacteria highlights the impact of social experience and the accompanying stress on gut microbiome with potentially similar effects in other social organisms. IMPORTANCEDisruptions in the gut microbiome negatively impact various systems in the body. Recently, the gut microbiome has been associated with neurological deficits in both behavioral and neurodegenerative disorders. Given the increasing prevalence in diagnosis of both neurological disease and behavioral disorders, researching the link between social behaviors and the gut microbiome is critical to better understand how the gut and the brain communicate during healthy and diseased states. Our research findings demonstrate the effects of social dominance and chronic stress on host gut microbiome composition. By identifying variations in bacterial relative abundance based on social experience and associated stress, a broader understanding of pathogenic (e.g., Enterobacteriaceae, Aeromonas) versus commensal communities (e.g., Exiguobacterium, Cetobacterium) and related host physiology can be inferred.

microbiology↗

bioRxiv2022

Increased adipose tissue indices of androgen catabolism and aromatization in women with metabolic dysfunction

BackgroundBody fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue. Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity. MethodsSamples from 40 bariatric candidates (31 women, 9 men) were included in the study. Visceral (VAT) and subcutaneous adipose tissue (SAT) were collected during surgery. Adipose tissue morphology was measured by a combination of histological staining and semi-automated quantification. Following extraction, intra-adipose and plasma steroid concentrations were determined by liquid chromatography, electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Aromatase activity was estimated using product-over-substrate ratio, while AKR1C2 activity was measured directly by fluorogenic probe. Gene expression was measured by quantitative PCR. ResultsVAT aromatase activity was positively associated with VAT adipocyte hypertrophy (p-valueadj < 0.01) and negatively with plasma HDL-cholesterol (p-valueadj < 0.01), while SAT aromatase activity predicted dyslipidemia in women even after adjustment for waist circumference, age and hormonal contraceptive use. We additionally compared women with high and low visceral adiposity index (VAI) and found that VAT excess is characterized by adipose tissue dysfunction, increased androgen catabolism mirrored by increased AKR1C2 activity and higher aromatase expression and activity indices. ConclusionIn women, increased androgen catabolism or aromatization is associated with visceral adiposity and adipose tissue dysfunction. DISCLOSURE SUMMARYAT obtained consulting fees form Bausch Health, Novo Nordisk and research funding from Johnson & Johnson Medical Companies as well as Medtronic and GI Windows for studies unrelated to this manuscript. The other authors have nothing to disclose.

physiology↗

bioRxiv2020

Sound generation in zebrafish with Bio-Opto-Acoustics (BOA)

Hearing is a crucial sense in underwater environments for communication, hunting, attracting mates, and detecting predators. However, the tools currently used to study hearing are limited, as they cannot controllably stimulate specific parts of the auditory system. To date, the contributions of hearing organs have been identified through lesion experiments that inactivate an organ, but this makes it difficult to gauge the specific stimuli to which each organ is sensitive, or the ways in which inputs from multiple organs are combined during perception. Here, we introduce Bio-Opto-Acoustic (BOA) stimulation, using optical forces to generate localized sound in vivo, and demonstrate stimulation of the auditory system of zebrafish larvae with unprecedented control. We use a rapidly oscillated optical trap to generate vibrations in individual otolith organs that are perceived as sound, while adjacent otoliths are either left unstimulated or similarly stimulated with a second optical laser trap. The resulting brain-wide neural activity is characterized using fluorescent calcium indicators, thus linking each otolith organ to its individual neuronal network in a way that would be impossible using traditional sound delivery methods. The results reveal integration and cooperation of the utricular and saccular otoliths, which were previously described as having separate biological functions, during hearing.

biophysics↗

bioRxiv2019

Brain-wide visual habituation networks in wild type and fmr1 zebrafish

Habituation is a form of learning during which animals stop responding to repetitive stimuli, and deficits in habituation are characteristics of several psychiatric disorders. Due to the technical challenges of measuring brain activity comprehensively and at cellular resolution, the brain-wide networks mediating habituation are poorly understood. Here we report brain-wide calcium imaging during visual learning in larval zebrafish as they habituate to repeated threatening loom stimuli. We show that different functional categories of loom-sensitive neurons are located in characteristic locations throughout the brain, and that both the functional properties of their networks and the resulting behavior can be modulated by stimulus saliency and timing. Using graph theory, we identify a principally visual circuit that habituates minimally, a moderately habituating midbrain population proposed to mediate the sensorimotor transformation, and downstream circuit elements responsible for higher order representations and the delivery of behavior. Zebrafish larvae carrying a mutation in the fmr1 gene have a systematic shift towards sustained premotor activity in this network, and show slower behavioral habituation. This represents the first description of a visual learning network across the brain at cellular resolution, and provides insights into the circuit-level changes that may occur in people with Fragile X syndrome and related psychiatric conditions.

neuroscience↗

bioRxiv2019

Altered brain-wide auditory networks in fmr1-mutant larval zebrafish

Altered sensory processing is characteristic of several psychiatric conditions, including autism and fragile X syndrome (FXS). Here, we use whole-brain calcium imaging at cellular resolution to map sensory processing in wild type larval zebrafish and mutants for fmr1, which causes FXS in humans. Using functional analyses and graph theory, we describe increased transmission and reduced filtering of auditory information, resulting in network-wide hypersensitivity analogous to the auditory phenotypes seen in FXS.

neuroscience↗